The long-term production of therapeutic proteins in the cerebral ventricles represents a recognized approach for neuroprotection in central nervous diseases. For example, intra-cerebroventricular (ICV) delivery of the VEGF (vascular endothelial growth factor) recombinant protein was reported to delay motor neuron degeneration in a rat model of amyotrophic lateral sclerosis (ALS) {Storkebaum, 2005 #22}. In this study, VEGF was delivered to the brain ventricles by stereotaxic implantation of a catheter linked to an osmotic minipump.
ICV injection of recombinant gene vectors is a convenient way to induce the continuous production of therapeutic proteins into the cerebrospinal fluid (CSF) through the transduction of the ependymal and choroids plexus cells {Broekman, 2007 #37}. This approach has been reported to be efficient for correction of the neuropathology in animal models of lysosomal diseases, by mediating gene delivery of lysosomal enzymes to the brain. For example, a recent study demonstrated that the direct neonatal ICV injection of an AAV expressing the lysosomal acid β-galactosidase was able to mediate the delivery of the enzyme to the brain and to restore normal levels of glycosphingo lipids {Broekman, 2007 #48}.
The delivery of proteins into the CSF thus represents an effective approach for the treatment of central nervous system (CNS) pathologies. However, the existing techniques to achieve such delivery require direct injection of gene vectors into the brain and/or surgery, and substantial risks related to the injection procedure (e.g., intracerebral surgery, infection or inflammation due to the blood brain barrier breaking, etc.), circumvent the clinical applications of this strategy.
WO2005/056807 relates to the identification of bovine AAV and proposes to use the same for gene delivery in vivo, including for treating CNS disorders. This application includes a discussion of the transcytosis property (i.e., active membrane transport) of AAV through the epithelium barrier. It is suggested the possibility of achieving CNS gene delivery either through ex vivo transplantation or injection of AAV-engineered cells, or through direct in vivo injection of the vectors.
However, the application is based on in vitro experiments showing Bovine AAV and AAV4 infection of bovine brain primary endothelia cells in culture.